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Prokineticin receptor antagonists and uses thereof

a technology of prokineticin and receptor, applied in the field of prokineticin receptor antagonists, can solve the problems of increased depression-like behaviors, impaired locomotor activity, body temperature and food intake,

Active Publication Date: 2014-05-13
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is directed to compounds, methods, and compositions that can treat and prevent type II diabetes and diabetic conditions. The compounds described herein are small molecule non-protein prokineticin antagonists that can target the prokineticin receptor, a pathway involved in pancreatic beta cell dysfunction. The compounds have a specific structure and are effective in treating and preventing diabetic conditions. The invention also includes a pharmaceutical composition containing a compound of Formula I for the treatment of diabetes and other related conditions. The compounds can be administered orally and can be used in the manufacture of a medicament for diagnosis or treatment of type II diabetes. Overall, the invention provides a novel approach for treating and preventing diabetic conditions through the targeting of the prokineticin receptor.

Problems solved by technology

ICV delivery of PK2 also led to increased depression-like behaviors in the tests of forced swimming and learned helplessness.
Furthermore, PK2− / − mice show impaired responses to exposure to new environments in terms of locomotor activity, arousal, body temperature and food intake.

Method used

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  • Prokineticin receptor antagonists and uses thereof
  • Prokineticin receptor antagonists and uses thereof
  • Prokineticin receptor antagonists and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0094]

(+)-(2S)-2-Amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide

[0095]Step 1: 3-chloro-4,5-dihydroxy benzaldehyde: A solution of 19.1 g 3-chloro-4-hydroxy-5-methoxy benzaldehyde in dichloromethane (1600 ml) was cooled in ice water bath. Boron tribromide (53.8 g) in dichloromethane (80 ml) were added and the mixture was stirred for two hours at ambient temperature and then was concentrated. The residue was cooled again with ice water bath and precipitated with ice-cold aqueous hydrochloric acid (1N, 500 ml). Solid residue was received upon filtration, then washed with ice water (500 ml) and dried in the air to obtain 19.3 g crude product of 3-chloro-4,5-dihydroxy benzaldehyde, which was used for the following step.

[0096]Step 2: 9-chloro-3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde: A mixture of 3-chloro-4,5-dihydroxy benzaldehyde (4.15 g), of 1,3-dibromopropane (4.71 g, 0.92 eq.) and potassium carbonate (8.28 g, 2.5 eq.) in acetonitrile (160 m...

example 2

[0100]

(±)-2-Methyl-3-(benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide

[0101]Step 1: (±)-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid: A mixture of (±)-2-Methyl-3-aminopropanoic acid (700 mg), di-tert-butyl pyrocarbonate (2.219 g), and triethylamine (1.375 g) in DCM (200 ml) was stirred over night in room temperature. The solvent was evaporated in vac and the solid residue was used for the next step.

[0102]Step 2: (±)-2-Methyl-3-(methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (600 mg), (±)-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (475 mg) and of dimethyl aminopyridine (284 mg) in DCM (30 ml) was stirred overnight. The reaction mixture was partitioned between ethyl aceta...

example 3

[0105]

(±)-2-Methyl-3-(benzyl(methyl)amino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide

[0106]Step 1: (±)-2-Methyl-3-(benzyl(methyl)amino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide: A mixture of (±)-2-Methyl-3-(benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (26 mg), paraformaldehye (16 mg), glacial acetic acid (90 μl) and sodium triacetoxyborohydride (26 mg) was dissolved in tetrahydrofuran (5 ml), and stirred overnight. The mixture was partitioned between aq. potassium carbonate (1N, 10 mL) and ethyl acetate (15 ml). The organic layer was concentrated and the residue was purified by flash chromatography on silica (40% ethyl acetate in hexane) to yield a resin: MS (m+1)=459.2; H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 2.00 (m, 1H), 2.05 (m, 1H), 2.25 (m, 2H), 2.30 (m, 3H), 2.55 (t, 1H), 2.65 (t, 1H), 2.90 (m, 1H), 3.05 (d, 1H), 3.25 (d, 1H), 3.60 (m, 2H), 4.15 (m, 2H), 4.35 ...

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Abstract

Contemplated compounds, compositions, and methods of prokineticin antagonists are presented where a prokineticin antagonist is used in the treatment and prevention of various conditions and disorders, and especially type II diabetes.

Description

[0001]This application claims priority to our copending U.S. provisional applications with the Ser. Nos. 61 / 138,433 and 61 / 219,226, which were filed Dec. 17, 2008 and Jun. 22, 2009, respectively, and which are incorporated by reference herein.[0002]This invention was made with government support under grant MH067753 awarded by the National Institute of Health. The government may have certain rights in the invention.FIELD OF THE INVENTION[0003]The field of the invention is directed to compounds and compositions that include a prokineticin antagonist and methods therefor.BACKGROUND OF THE INVENTION[0004]Prokineticins are regulatory peptides that are thought to exert signaling activity via two highly conserved G protein-coupled receptors (GPCR), the prokineticin receptor 1 (PKR1) and the prokineticin receptor 2 (PKR2). Mature human prokineticins (PK1 and PK2) contain 86 and 81 amino acids, respectively, and are among the largest known ligands for all GPCRs. PK1 and PK2 share about 45% ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07C233/02C07D213/36
CPCC07D321/10C07D405/12C07D417/12A61P1/00A61P3/10A61P9/10A61P25/00A61P25/04A61P25/20A61P25/22
Inventor ZHOU, QUN-YONGLI, JIA-DAHUANG, QI
Owner RGT UNIV OF CALIFORNIA
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